Role of RNA modifications in cancer

Nature reviews. Cancer, Journal Year: 2020, Volume and Issue: 20(6), P. 303 - 322

Published: April 16, 2020

Language: Английский

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Targeting the progression of chronic kidney disease

Nature Reviews Nephrology, Journal Year: 2020, Volume and Issue: 16(5), P. 269 - 288

Published: Feb. 14, 2020

Language: Английский

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Deciphering miRNAs’ Action through miRNA Editing

International Journal of Molecular Sciences, Journal Year: 2019, Volume and Issue: 20(24), P. 6249 - 6249

Published: Dec. 11, 2019

MicroRNAs (miRNAs) are small non-coding RNAs with the capability of modulating gene expression at post-transcriptional level either by inhibiting messenger RNA (mRNA) translation or promoting mRNA degradation. The outcome a myriad physiological processes and pathologies, including cancer, cardiovascular metabolic diseases, relies highly on miRNAs. However, deciphering precise roles specific miRNAs in these pathophysiological contexts is challenging due to high levels complexity their actions. Indeed, regulation frequently cell/organ specific; dependent stress status organism; often poorly correlated miRNA levels. Such biological features suggest that various regulatory mechanisms control not only expression, but also activity and/or bioavailability. Several have been described modulate action, genetic polymorphisms, methylation promoters, asymmetric strand selection, interactions RNA-binding proteins (RBPs) other coding/non-coding RNAs. Moreover, nucleotide modifications (A-to-I C-to-U) within sequences different stages maturation critical for functionality. This mechanism called "RNA editing" involves enzymes adenosine/cytidine deaminase family, which trigger single changes primary These greatly influence miRNA's stability, changing its specificity towards target mRNAs. Understanding how editing events impact ability regulate responses cells organs, development e.g., diseases should deepen our knowledge molecular underlying complex can facilitate design new therapeutic approaches based targeting. Herein, we will discuss current this regulates biogenesis activity.

Language: Английский

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Emerging concepts of miRNA therapeutics: from cells to clinic

Trends in Genetics, Journal Year: 2022, Volume and Issue: 38(6), P. 613 - 626

Published: March 15, 2022

Single microRNAs (miRNAs) regulate large subsets of mRNA targets. Although this property makes miRNAs potentially a powerful therapeutic tool, it also represents major challenge in terms controlling adverse effects that have been observed clinical trials.Besides systemic applications via injection and infusion, advanced strategies emerge for miRNA-based drug administration implantable 3D matrices, inhalation schemes, intake food.A combination miRNA therapeutics with chemical modifications, biomolecule conjugation, or the use carriers improves site-directed efficient cell targeting.A comprehensive risk assessment is required before any vivo targeting to minimize off-target avoid overdosing miRNAs. MicroRNAs are very genetic regulators, as evidenced by fact single can direct entire cellular pathways interacting broad spectrum target genes. This renders highly interesting tools restore functions altered part disease phenotype. However, strength weakness because their so numerous hardly be avoided. In review, we point out main challenges specifically address problems need surmounted push toward application Particular emphasis given approaches already found way into studies. What promises therapeutics?miRNAs (see Glossary) small, noncoding RNAs serve post-transcriptional regulators protein encoding There more than 2300 different human cells time- tissue-dependent expression patterns [1.Alles J. et al.An estimate total number true miRNAs.Nucleic Acids Res. 2019; 47: 3353-3364Crossref PubMed Scopus (207) Google Scholar, 2.Kozomara A. al.miRBase: From microRNA sequences function.Nucleic D155-D162Crossref (1326) 3.Ludwig N. al.Distribution across tissues.Nucleic 2016; 44: 3865-3877Crossref (529) Scholar]. Essential aspects biogenesis its functionality provided Box 1. Criteria fidelity addressed below.Box 1Cellular biogenesismiRNA located exons introns protein-encoding genes intergenic regions. They coregulated together host under control own promoters [103.Olena A.F. Patton J.G. Genomic organization microRNAs.J. Cell. Physiol. 2010; 222: 540-545PubMed During (thoroughly reviewed elsewhere, e.g., 104.Ha M. Kim V.N. Regulation biogenesis.Nat. Rev. Mol. Cell Biol. 2014; 15: 509-524Crossref (3208) 105.Winter al.Many roads maturity: MicroRNA regulation.Nat. 2009; 11: 228-234Crossref (1970) Scholar]), transcribed RNA polymerase II III form primary (pri-miRNAs), which up several thousand nucleotides length shaped hairpin structure. pri-miRNAs further processed Drosha-DGCR8 microprocessor complex nucleus generate an precursor (pre-miRNA) approximately 70 length. noncanonical biogenesis, intron-encoded pre-miRNAs (mirtrons) directly along coencoded transcripts through spliceosomes. The pre-miRNA exported exportin-5 cytoplasm, where cleaved duplex 22 RNase Dicer double-stranded binding enzyme TRBP. strands subsequently incorporated RISC, allowing ribonucleoprotein bind usually within 3′ untranslated regions mRNAs. Reverse complementary takes place seed region, situated at 2 7 miRNA's 5′ end. results inhibition abrogation translation process. It estimated 60% all subject regulation [106.Friedman R.C. al.Most mammalian mRNAs conserved targets microRNAs.Genome 19: 92-105Crossref (6022) Scholar], making central signaling widespread impact on almost every biological process [6.Gebert L.F.R. MacRae I.J. function animals.Nat. 20: 21-37Crossref (893) Besides level, there recent evidence translocate transcription efficiency specific genes, enhancing networks [107.Liu H. al.Nuclear gene regulation, immunity cancer.Mol. Cancer. 2018; 17: 64Crossref (167) Scholar].Physiological changes pivotal consequence cascades. many scenarios, plays likewise role modifying pathological [4.Subramanian S. Steer C.J. Special issue: health disease.Genes (Basel). 10Crossref (10) diagnostic potential levels, these small offer themselves purposes targeted manipulation crucial phenotype [5.Huang W. MicroRNAs: Biomarkers, diagnostics, therapeutics.Methods 2017; 1617: 57-67Crossref (100) intervention most efficient, consequently especially attractive, regulated Thus, spite relatively moderate effect each shown miR-34a-5p has identified hub T Scholar,7.Hart al.miR-34a networks.J. Immunother. 7: 187Crossref (19) Vice versa, one pathway typically miRNAs, resulting regulatory network, addressing majority molecular pathomechanisms humans.Against background, not surprising that, according records, since 2015, 600 articles published heading 'miRNA-based therapeutics'. future undoubtedly appealing, still great practical difficulties overcome, including identification proper routes, in-body stability, tissues types, attaining intended intracellular effects. Hence, only few drugs have, now, entered test phase (Table 1). following sections, effective nonhazardous therapeutics. We particularly emphasize preclinical studies developed associated using therapeutics.Table 1Clinical trials therapeuticsaNCT numbered registered ClinicalTrials.gov; EudraCT EU Clinical Trials Register (clinicaltrialsregister.eu).miRNA nameTargeted miRNAMode actionBackground diseaseBody application/permission uptakeClinical trial number(s)RefsAMT-130bPhase I ongoing.Artificial miRNAamiRNA expressionHuntington diseaseStereotaxic infusion/viral transfer (adeno-associated vector)NCT04120493[23.Keskin al.AAV5-miHTT lowers huntingtin without patient-derived neuronal cultures astrocytes.Mol. Ther. Methods Clin. Dev. 275-284Abstract Full Text PDF (20) 24.Miniarikova al.Design, characterization, lead selection development therapy Huntington's disease.Mol. Nucleic Acids. 5e297Abstract (64) 25.Samaranch L. al.MR-guided parenchymal delivery adeno-associated viral vector serotype 5 non-human primate brain.Gene 24: 253-261Crossref (41) Scholar]RG-012/lademirsen/SAR339375cPhase ongoing.miR-21Anti-miRAlport syndromeSubcutaneous injection/chemical modification (phosphorothioate)NCT03373786, NCT02855268[70.Gomez I.G. al.Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression stimulating metabolic pathways.J. Invest. 2015; 125: 141-156Crossref (246) Scholar,76.Kelnar K. al.Quantification mimics whole blood from nonhuman primates.Anal. Chem. 86: 1534-1542Crossref (49) Scholar,122.Kashtan C.E. Gross O. practice recommendations diagnosis management syndrome children, adolescents, young adults – update 2020.Pediatr. Nephrol. 2021; 36: 711-719Crossref (14) Scholar,123.Kashtan Correction to: adults-an 731Crossref (2) Scholar]RG-125/AZD4076dPhase completed.miR-103/107Anti-miRNonalcoholic steatohepatitis (NASH) patients type diabetes/prediabetesSubcutaneous injection/biomolecule conjugation (GalNAc)NCT02612662, NCT02826525[76.Kelnar 77.Drenth J.P.H. Schattenberg J.M. nonalcoholic graveyard: Established hurdles planning success.Expert Opin. Investig. Drugs. 2020; 29: 1365-1375Crossref (16) 78.Huang Y. Preclinical advances GalNAc-decorated nucleic acid therapeutics.Mol. 6: 116-132Abstract (171) Scholar]MRG-110dPhase completed.miR-92aAnti-miRWoundsSkin (LNA)NCT03603431[124.Gallant-Behm C.L. al.A synthetic microRNA-92a inhibitor (MRG-110) accelerates angiogenesis wound healing diabetic nondiabetic wounds.Wound Repair Regen. 26: 311-323Crossref (46) Scholar,125.Abplanalp W.T. al.Efficiency derepression anti-miR-92a: Results first study.Nucleic Acid 30: 335-345Crossref (32) Scholar]MesomiR 1dPhase completed.miR-16miRNA mimicMalignant pleural mesothelioma, non–small lung cancerIntravenously/vehicle (nonliving minicells)NCT02369198[56.Reid G. al.Clinical TargomiRs, mimic-based treatment recurrent thoracic cancer.Epigenomics. 8: 1079-1085Crossref (120) Scholar,57.van Zandwijk al.Safety activity microRNA-loaded minicells malignant mesothelioma: A first-in-man, 1, open-label, dose-escalation study.Lancet Oncol. 18: 1386-1396Abstract (316) Scholar,126.Reid al.Restoring miR-16: novel approach mesothelioma.Ann. 2013; 3128-3135Abstract (158) Scholar]CDR132LdPhase completed.miR-132Anti-miRHeart failureIntravenously/chemical (LNA)NCT04045405[127.Taubel al.Novel antisense microRNA-132 heart failure: first-in-human 1b randomized, double-blind, placebo-controlled study.Eur. Heart 42: 178-188Crossref (47) Scholar,128.Batkai al.CDR132L systolic diastolic animal model chronic failure.Eur. 192-201Crossref (22) Scholar]Remlarsen/MRG-201ePhase completed.miR-29miRNA mimicKeloid disorderSkin (cholesterol)NCT02603224, NCT03601052[73.Gallant-Behm microRNA-29 mimic (remlarsen) represses extracellular matrix fibroplasia skin.J. Dermatol. 139: 1073-1081Abstract (74) Scholar,103.Olena Scholar,104.Ha Scholar]Miravirsen/SPC3649ePhase completed., fUnknown status.miR-122Anti-miRChronic hepatitis C virusSubcutaneous (LNA)NCT02508090, NCT02452814, NCT01200420, NCT01872936, NCT01727934, NCT01646489[16.Ottosen al.In vitro antiviral resistance profile miravirsen, anti-hepatitis virus factor miR-122.Antimicrob. Agents Chemother. 59: 599-608Crossref (130) Scholar,129.Gebert L.F. al.Miravirsen (SPC3649) inhibit miR-122.Nucleic 609-621Crossref (228) 130.Elmen al.LNA-mediated silencing primates.Nature. 2008; 452: 896-899Crossref (1381) 131.Lanford R.E. al.Therapeutic microRNA-122 primates infection.Science. 327: 198-201Crossref (1427) 132.Janssen H.L. al.Treatment HCV infection microRNA.N. Engl. Med. 368: 1685-1694Crossref (1644) Scholar]MRX34gStopped/terminated.miR-34amiRNA mimicSolid tumors (e.g., hepatocellular carcinoma), melanomaIntravenously/vehicle (liposomal)NCT01829971, NCT02862145[29.Beg M.S. al.Phase study MRX34, liposomal miR-34a mimic, administered twice weekly solid tumors.Investig. New 35: 180-188Crossref (468) Scholar,32.Daige al.Systemic miR34a liver Cancer 13: 2352-2360Crossref (112) Scholar,133.Huang H.Y. al.miRTarBase 2020: Updates experimentally validated microRNA-target interaction database.Nucleic 48: D148-D154PubMed Scholar]RG-101gStopped/terminated.miR-122Anti-miRChronic (GalNAc)EudraCT numbers 2015-001535-21, 2015-004702-42, 2016-002069-77[76.Kelnar Scholar,79.van der Ree M.H. al.Safety, tolerability, RG-101 C: 1B, randomised controlled trial.Lancet. 389: 709-717Abstract (143) Scholar,80.Stelma F. al.Immune natural killer who received dose anti-microRNA-122, RG-101.Hepatology. 66: 57-68Crossref (23) Scholar]Cobomarsen/MRG-106gStopped/terminated.miR-155Anti-miRMycosis fungoidesIntravenously/chemical (LNA)NCT02580552, NCT03713320, NCT03837457[134.Seto A.G. al.Cobomarsen, oligonucleotide miR-155, co-ordinately regulates multiple survival reduce proliferation cutaneous T-cell lymphoma.Br. Haematol. 183: 428-444Crossref (126) 135.James A.M. al.SOLAR: 2, global, active comparator investigate efficacy safety cobomarsen subjects mycosis fungoides (MF) [abstract].Hematol. 37: 562-563Crossref 136.Querfeld C. al.Preliminary 1 evaluating MRG-106, antagonist (LNA antimiR) microRNA-155, CTCL.Blood. 128: 1829Crossref Scholar]a NCT (clinicaltrialsregister.eu).b Phase ongoing.c ongoing.d completed.e completed.f Unknown status.g Stopped/terminated. Open table new tab How modify expression?The general aim ideally reverse changes. includes enhancement reconstitution endogenous act suppressors expressional reduction functional blocking drivers. To acids commonly used (Figure 1), (miRNA mimics), recombinant vectors carrying sequences, oligonucleotide-based inhibitors (anti-miRs) [8.van Rooij E. Kauppinen Development coming age.EMBO 851-864Crossref (433) Scholar].One currently pursued permeable molecules. These molecules exert by, example, proteins involved miRNA-specific secondary structures [9.Fan R. al.Small big roles biology microRNA-targeted therapeutics.RNA 16: 707-718Crossref Small designed aid bioinformatics experimental screening pharmacologically compounds [10.Disney M.D. al.Inforna 2.0: platform sequence-based design structured RNAs.ACS 1720-1728Crossref (95) Scholar,11.Suresh B.M. fragment-based identify optimize bioactive ligands RNA.Proc. Natl. Acad. Sci. U. 117: 33197-33203Crossref (0) example oncogenic miR-21. was target-oriented various low-molecular-weight [11.Suresh Natural rich source interfering [12.Alnuqaydan Targeting micro-RNAs products: strategy combat cancer.Am. Transl. 12: 3531-3556PubMed Curcumin has, breast cancer growth [13.Norouzi al.Curcumin adjunct modulator cancer.Curr. Pharm. Des. 171-177Crossref (35) Scholar].A combine treatments conventional drugs. drug-based therapies improved interventions pathways, affect outcomes [14.Seo H.A. al.MicroRNA-based combinatorial therapy: Effects anti-cancer therapies.Cells. 9: 29Crossref Liver-specific miR-122 considered driver (HCV) maintenance hepatocytes [15.Panigrahi al.miR-122 affects both initiation infections.J. Virol. 96e0190321PubMed (ClinicalTrials.gov identifiers NCT01872936), against counteracted combining miravirsen/SPC3649 [16.Ottosen Combined schemas chemotherapeutics manipulators being improvement antitumor therapies, common cancers such [17.Gong al.Functional exosome-mediated co-delivery doxorubicin hydrophobically modified 159 triple-negative therapy.J. Nanobiotechnol. 93Crossref (93) Scholar,18.Saatci al.Targeting lysyl oxidase (LOX) overcomes chemotherapy triple negative cancer.Nat. Commun. 2416Crossref (62) Scholar].The combined siRNAs offers another route improve constitute group conceived [19.Lam J.K. al.siRNA versus silencing.Mol. 4e252Abstract (465) establishment siRNA [20.Zhang al.The risks therapeutics: perspective.Drug Devel. 721-733Crossref (40) achieved coexpression plasmid, recently [21.Petrek al.Bioengineering long molecule carries RNAs.Appl. Microbiol. Biotechnol. 103: 6107-6117Crossref (13) Scholar].Artificially constructs, referred 'amiRNAs,' promise advancement amiRNAs combinations scaffolds transcripts. While show high specificity, siRNA-based design, processing ensured structure [22.Kotowska-Zimmer al.Artificial tools: Challenges opportunities.Wiley Interdiscip. RNA. 12e1640Crossref (3) An amiRNA-based (AMT-130) sequence Huntingtin pri-miR-451 scaffold employed identifier NCT04120493) [23.Keskin Scholar].miRNA sponges option manipulate levels constructs harboring sites. sequestration effectiveness sponges, circular RNAs, analyzed artificially sponge, six alternating sites miR-132 miR-212, tested, mouse models cardiovascular diseases [26.Lavenniah al.Engineered attenuate pressure overload-induced cardiac hypertrophy.Mol. 28: 1506-1517Abstract (45) Additional highlight naturally occurring therapeutically usable sponges. Recently, hsa_circ_0120472, two predicted sites, sponge miR-550a [27.Meng al.Circular circCCDC85A inhibits acting miR-550a-5p enhance MOB1A expression.Breast 2022; 1Crossref yet increasing will certainly promote approaches.What severe side therapeutics?Depending chosen warrant delivery, necessarily restricted tissue but cause prominent occurrence disastrous mimic. MRX34 tumor NCT01829971), hematologic malignancies, had terminated prematurely immune-related causing death four [28.Hong D.S. tumours.Br. 122: 1630-1637Crossref (183) Scholar,29.Beg make properties suppressor [30.Saito al.microRNA-34a agent cancer.J. 4: 1951-1959Crossref systemically amphoteric (i.e., pH-dependent) strategy, supposed take low-pH environment tumorous [31.Bouchie First enters clinic.Nat. 31: 577Crossref Animal models, however, showed uptake bone marrow spleen [32.Daige Scholar,33.Kelnar Bader qRT-PCR method determining biodistribution mimic.Methods 1317: 125-133Crossref (11) known generation preservation immune cells. Accordingly, context testing, dose-dependent modulation white now evident impacts cells, regulating calcium chemokine [3

Language: Английский

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Circular RNAs in Cancer: Biogenesis, Function, and Clinical Significance

Trends in cancer, Journal Year: 2020, Volume and Issue: 6(4), P. 319 - 336

Published: Feb. 19, 2020

Language: Английский

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Post-transcriptional control of miRNA biogenesis

RNA, Journal Year: 2018, Volume and Issue: 25(1), P. 1 - 16

Published: Oct. 17, 2018

MicroRNAs (miRNAs) are important regulators of gene expression that bind complementary target mRNAs and repress their expression. Precursor miRNA molecules undergo nuclear cytoplasmic processing events, carried out by the endoribonucleases DROSHA DICER, respectively, to produce mature miRNAs loaded onto RISC (RNA-induced silencing complex) exert biological function. Regulation levels is critical in development, differentiation, disease, as demonstrated multiple control during biogenesis cascade. Here, we will focus on post-transcriptional mechanisms discuss impact cis -acting sequences precursor miRNAs, well trans factors these precursors influence processing. In particular, highlight role general RNA-binding proteins (RBPs) specific revealing a complex layer regulation production

Language: Английский

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miRNA interplay: mechanisms and consequences in cancer

Disease Models & Mechanisms, Journal Year: 2021, Volume and Issue: 14(4)

Published: April 1, 2021

ABSTRACT Canonically, microRNAs (miRNAs) control mRNA expression. However, studies have shown that miRNAs are also capable of targeting non-coding RNAs, including long RNAs and miRNAs. The latter, termed a miRNA:miRNA interaction, is form self-regulation. In this Review, we discuss the three main modes regulation: direct, indirect global interactions, their implications in cancer biology. We cell-type-specific nature current experimental approaches bioinformatic techniques, how these strategies not sufficient for identification novel interactions. self-regulation impact on gene regulation has yet to be fully understood. Investigating hidden world miRNA will assist discovering regulatory mechanisms associated with disease pathways.

Language: Английский

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miRNA-based biomarkers, therapies, and resistance in Cancer

International Journal of Biological Sciences, Journal Year: 2020, Volume and Issue: 16(14), P. 2628 - 2647

Published: Jan. 1, 2020

MicroRNAs (miRNAs), small non-coding RNAs (ncRNAs) of about 22 nucleotides in size, play important roles gene regulation, and their dysregulation is implicated human diseases including cancer.A variety miRNAs could take the cancer progression, participate process tumor immune, function with miRNA sponges.During last two decades, connection between various cancers has been widely researched.Based on evidence miRNA, numerous potential biomarkers for diagnosis prognosis have put forward, providing a new perspective screening.Besides, there are several miRNA-based therapies among different being conducted, advanced treatments such as combination synergistic strategies use complementary provide significant clinical benefits to patients potentially.Furthermore, it demonstrated that many engaged resistance complex underlying regulatory mechanisms, whose comprehensive cognition can help clinicians improve patient prognosis.With belief studies would great implications, we attempt summarize current situation development prospects this review.

Language: Английский

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The multi-factorial nature of clinical multidrug resistance in cancer

Drug Resistance Updates, Journal Year: 2019, Volume and Issue: 46, P. 100645 - 100645

Published: Sept. 1, 2019

Language: Английский

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The maternal-to-zygotic transition revisited

Development, Journal Year: 2019, Volume and Issue: 146(11)

Published: June 1, 2019

The development of animal embryos is initially directed by maternal gene products. Then, during the maternal-to-zygotic transition (MZT), developmental control handed to zygotic genome. Extensive research in both vertebrate and invertebrate model organisms has revealed that MZT can be subdivided into two phases, which very different modes regulation are implemented: initially, exclusively post-transcriptional post-translational, following gradual activation genome leads predominance transcriptional regulation. These changes expression program precisely controlled highly interconnected. Here, we review current understanding mechanisms underlie handover MZT.

Language: Английский

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